Aspartylglucosaminuria via the AGA Gene
- Summary and Pricing
- Clinical Features and Genetics
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AGA is the only gene known to be causative for aspartylglucosaminuria. A specific mutation (Cys163Ser) is concentrated in over 98% of the Finnish population. So far there are about 30 other rare family AGA alleles that have been characterized at the molecular level in the world's population.
Aspartylglucosaminuria (AGU) is a severe lysosomal storage disorder that involves the central nervous system and causes skeletal abnormalities as well as connective tissue lesions. The most characteristic feature is progressive mental retardation. Affected individuals tend to have a characteristic facial appearance that includes widely spaced eyes (ocular hypertelorism), small ears, and full lips. People with this condition may also have bones that become progressively weak and prone to fracture (osteoporosis), an unusually large range of joint movement (hypermobility), and loose skin. Individuals with AGU appear normal during infancy and have a lifespan of about 25 to 45 years (Aronson 1999).
Aspartylglucosaminuria is a rare autosomal recessive disorder present mostly in the Finnish population (Aronson 1999) with an incidence of 1 in 18,500, with about 200 reported cases and a carrier frequency of 2.5-3%. The incidence in the rest of the world population is unknown. AGU is caused by mutations in the aspartylglucosaminidase (AGA) gene. AGA is responsible for the production of a lysozomal enzyme aspartylglucosaminidase, which is involved in the breakdown of complexes of sugar molecules (oligosaccharides) attached to proteins (glycoproteins). AGA mutations result in the absence or shortage of the AGA enzyme in lysosomes, preventing the normal breakdown of glycoproteins. As a result, glycoproteins buildup, disrupting normal functions of the cell and can result in destruction of the cell, particularly nerve cells in the brain. Loss of these cells causes many of the signs and symptoms of aspartylglucosaminuria.
A specific mutation (Cys163Ser) has been identified in over 98% of the affected Finnish population. So far there are about 30 other rare family AGA alleles that have been characterized at the molecular level in the world's population. Causative mutations include missense, nonsense, splicing, and small deletions and insertions.
This test involves bidirectional Sanger DNA sequencing of all coding exons of AGA. The entire coding region and ~20 bp of flanking non-coding DNA on either side of each splice site are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
Individuals affected with progressive mental retardation, skeletal abnormalities and characteristic facial features should be considered for testing for Aspartylglucosaminuria.
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- Genetic Counselor Team - firstname.lastname@example.org
- McKenna Kyriss, PhD - email@example.com
- Aronson NN Jr. 1999. Aspartylglycosaminuria: biochemistry and molecular biology. Biochim. Biophys. Acta 1455: 139–154. PubMed ID: 10571008
Bi-Directional Sanger Sequencing
Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org). As required, DNA is extracted from the patient specimen. PCR is used to amplify the indicated exons plus additional flanking non-coding sequence. After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions. In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.
As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.
Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).
In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.
Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.
In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.
In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.
Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.
Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.
Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.
myPrevent - Online Ordering
- The test can be added to your online orders in the Summary and Pricing section.
- Once the test has been added log in to myPrevent to fill out an online requisition form.
- A completed requisition form must accompany all specimens.
- Billing information along with specimen and shipping instructions are within the requisition form.
- All testing must be ordered by a qualified healthcare provider.
(Delivery accepted Monday - Saturday)
- Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
- For small babies, we require a minimum of 1 ml of blood.
- Only one blood tube is required for multiple tests.
- Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
- During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
- In cold weather, include an unfrozen ice pack in the shipping container as insulation.
- At room temperature, blood specimen is stable for up to 48 hours.
- If refrigerated, blood specimen is stable for up to one week.
- Label the tube with the patient name, date of birth and/or ID number.
(Delivery accepted Monday - Saturday)
- Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
- For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
- DNA may be shipped at room temperature.
- Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
- We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.
(Delivery preferred Monday - Thursday)
- PreventionGenetics should be notified in advance of arrival of a cell culture.
- Culture and send at least two T25 flasks of confluent cells.
- Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
- Send specimens in insulated, shatterproof container overnight.
- Cell cultures may be shipped at room temperature or refrigerated.
- Label the flasks with the patient name, date of birth, and/or ID number.
- We strongly recommend maintaining a local back-up culture. We do not culture cells.